WNT1-inducible-signaling pathway protein 1 (WISP1) is a target gene of the WNT signaling pathway. WNT signaling plays a role in lung development, regulating both epithelial and mesenchymal development via autocrine and paracrine signals. In brief, WNT proteins bind to Frizzled (Fz) cell surface receptors. Fz receptors are seven-pass transmembrane receptors. In addition to Fz proteins, single-pass transmembrane proteins such as low-density lipoprotein receptor-related protein 5 and 6 (LRP5, LRP6), receptor tyrosine kinase (RTK)-like orphan receptor 1 or 2 (Ror1, Ror2) and receptor-like tyrosine kinase (Ryk) have been shown to function as co-receptors for WNT signaling. The inhibition of glycogen synthase kinase 3β (GSK3β) results in the hypophosphorylation of β-catenin that allows translocation of this cytoskeletal protein into the nucleus. Subsequent binding of β-catenin to the LEC/TCF family of transcription factors converts them from transcriptional repressors to activators.
WNTs constitute a large family of cysteine-rich secreted ligands that are essential for a wide array of developmental and physiological processes. At least 19 WNT members have been found in humans and mice, and they exhibit unique expression patterns and distinct functions during development. WNTs control various cellular functions including proliferation, differentiation, death, migration, and polarity, by activating multiple intracellular signaling cascades, including the βcatenin-dependent and -independent pathways. WNTs have been divided classically into two distinct types based on their ability to induce transformation of the mouse mammary epithelial cell line C57MG. Highly transforming members include WNT1, WNT3, WNT3a, and WNT7a, and intermediately transforming or nontransforming members include WNT2, WNT4, WNT5a, WNT5b, WNT6, WNT7b, and WNT11.
WISP1 expression is altered during lung development. In particular, high WISP1 expression was observed during organogenesis and respiratory tree formation (pseudoglandular stage), while WISP1 expression was lower during epithelial differentiation (canalicular stage). Human WISP1 protein expression is induced by β-catenin in response to WNT1 and WNT3a. Furthermore, WISP1 is induced in murine and human lung cells by TGF. Further, while WISP1 has been shown to increase cell proliferation, additional elements (e.g., TGF-β) may be needed to induce differentiation.
Elevated WISP1 expression has been described in several diseases including hepatocellular carcinoma, colon adenocarcinomas, lung carcinoma and breast cancer. WISP1 expression has also been associated with nonmalignant diseases of the heart, bone and lung. Increased WISP1 levels were found in the synovium and cartilage in experimental osteoarthritis, in cardiomyocytes and cardiac fibroblasts in the border zone and non-infarcted region after experimental myocardial infarction, and in alveolar epithelium in experimental and human idiopathic pulmonary fibrosis (IPF).
WISP1 is upregulated at the alveolar epithelial surface in the human IPF lung, and strong nuclear β-catenin immunoreactivity was observed in fibroblasts within fibrotic foci and proliferative bronchiolar and alveolar lesions; findings not observed in the normal lung. Further support for the importance of the WNT signaling pathway in the pathogenesis of IPF stems from the observation that mice deficient in matrilysin (MMP7), a target gene of the β-catenin-LEF1 signaling pathway, are protected from bleomycin-induced fibrosis. Notably, WISP1 mediates pulmonary fibrosis in mice and pharmacological neutralization of WISP1 (with a mouse anti-WISP1 antibody) markedly attenuates bleomycin-induced pulmonary fibrosis in vivo.
IPF is a fibroproliferative disorder proceeded by alveolar epithelial injury and activation with fibrotic foci. Therefore, there is a need in the art for an effective, strong-binding, fully human antibody product that can bind to WISP1 and be an effective treatment for a number of pulmonary and neoplastic diseases. The present disclosure provides an initial achievement of such a need.